The beneficial effects of daily vitamin D appear to have diminished after the supplement was stopped, while the protection from n-3 FA persisted for at least two more years, two years after the conclusion of a randomized trial that demonstrated the benefit of n-3 FA and vitamin D supplementation for lowering risk for autoimmune diseases.
As previously reported, five years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and five years of n-3 FA supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases. The randomized VITAL study was designed primarily to investigate the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease.
The benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant, according to investigators Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston, Massachusetts, and colleagues. Among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant.
“VITAL observational extension results suggest that vitamin D supplementation should be given on a continuous basis for long-term prevention of [autoimmune diseases]. The beneficial effects of n-3 fatty acids, however, may be prolonged for at least 2 years after discontinuation,”
Costenbader told that the results of the observational extension study suggest that the benefits of vitamin D “wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years.”
The researchers observed variations in the effects across various autoimmune disorders in addition to changes in the duration of the protective impact.
“The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease,” she stated.
While each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients, according to Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona. Funk was not involved in the study.
“I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions,” she said.
“[T]he studies by Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease],” rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote in an editorial that accompanied the study. The enduring advantages they mention, which last for up to two years after the supplements are stopped, align with the chronic nature of FA species in cellular plasma membranes, where they act as substrates for a wide range of noteworthy metabolic and inflammatory processes.”
Costenbader and colleagues tacked an accessory research onto the VITAL trial, which included primary outcomes of cancer and cardiovascular disease incidence, to investigate whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time.
A total of 25,871 participants were enrolled, comprising 13,085 women and 12,786 men who were 55 years of age or older. With a 2 × 2 factorial design, patients were first randomly assigned to receive 2000 IU/d of vitamin D or a placebo. In both the primary randomization arms for the vitamin D and placebo, patients were subsequently randomized to receive 1 g/d of n-3 FAs or a placebo.
After adjusting for age, sex, race, and other supplement arm in a multivariate analysis, vitamin D by itself was linked to an incident autoimmune disease hazard ratio (HR) of 0.68 (P =.02), n-3 by itself to a nonsignificant HR of 0.74, and the combination to an HR of 0.69 (P =.03). However, the effect of n-3 became substantial (HR = 0.82) when instances of probable incident autoimmune illness were added.
Costenbader and colleagues presented observational data on 21,592 VITAL participants in the current research. This sample included 87.9% of those who were still alive and able to be contacted at the end of the study, as well as 83.5% of those who were initially randomized.
During the randomized follow-up, the researchers assessed incident autoimmune illnesses using annual questionnaires, just as they did in the original trial. Participants were questioned regarding psoriasis, autoimmune thyroid disease, polymyalgia rheumatica, inflammatory bowel disease, and rheumatoid arthritis with a recent onset and a doctor’s diagnosis. Additionally, participants could list any additional diagnoses of autoimmune diseases.
Since the study data were first published, 236 new cases of proven autoimmune illness have been reported. Additionally, 65 possible cases were found during the median 5.3-year randomized part, and 42 probable cases were discovered during the 2-year observational phase.
After a 2-year monitoring period, the researchers discovered that, out of the 259 patients who were initially randomized to receive a vitamin D placebo, 255 participants who received vitamin D had a newly established, proven autoimmune illness. This resulted in an HR of 0.98 that was not significant.
The addition of likely autoimmune cases to the confirmed instances did not significantly alter the adjusted HR, which was 0.95.
On the other hand, patients initially assigned to n-3 had 234 confirmed cases of autoimmune illness, compared to 280 patients randomly assigned to the n-3 placebo. This difference resulted in a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.
The use of levels meant to prevent cancer or cardiovascular disease, as stated by Costenbader and colleagues, limited the study, and higher doses meant for high-risk or nutritionally deficient groups might show stronger effects of supplementing. They also pointed out that pinpointing the exact moment and commencement of incident disease is challenging, and that in-depth assessments of specific autoimmune diseases were not possible due to the small number of instances that transpired over the 2-year observational period.